Next-generation Biologics in the Management of Plaque Psoriasis: A Literature Review of IL-17 Inhibition
March 2015 | Volume 14 | Issue 3 | Original Article | 244 | Copyright © March 2015
Paul S. Yamauchi MD PhDa and Jerry Bagel MDb
aDavid Geffen School of Medicine at UCLA, Dermatology Institute & Skin Care Center, Inc., Clinical Science Institute, Santa Monica, CA
bPsoriasis Treatment Center of Central New Jersey, East Windsor, NJ
Advances in the understanding of the pathogenesis of psoriasis have led to the development of biologic agents that target T cells and cytokines that play a specific role in the underlying inflammation associated with psoriasis (eg, tumor necrosis factor-α inhibitors, interleukin [IL]-12/23 inhibitors). In this review, evidence for the central role of IL-17 in the pathophysiology of psoriasis is presented, along with available clinical trial data on the selective IL-17 inhibitors in development. Three biologic agents that target IL-17 are currently in clinical development: secukinumab, ixekizumab, and brodalumab. Clinical studies to date suggest a favorable safety profile and the potential for better efficacy over the previous generation of agents, with Psoriasis Area Severity Index 75 response rates of up to 80% or greater. Fully published results of phase III studies of these agents are eagerly awaited. J Drugs Dermatol.
Psoriasis is a chronic inflammatory skin disease with a worldwide prevalence in adults ranging from approximately 1% to 3% (United States, United Kingdom, Croatia, and Italy) up to 8.5% (Norway).1 Plaque psoriasis (ie, psoriasis vulgaris) is the most common form of the disease, accounting for more than 80% of all cases.2,3 Patients with mild plaque psoriasis (eg, <3% body surface area affected) can generally manage their condition using topical agents, with options that include corticosteroids, vitamin D analogues, retinoids, and coal-tar-containing products.4,5 For more severe disease (affecting more than 10% body surface area), phototherapy and conventional systemic therapies (eg, methotrexate, cyclosporine, acitretin, and fumaric acid derivatives) are often used. However, acute or long-term use of some of the current oral agents can be associated with potentially serious side effects, including organ toxicity.5-7
Advances in the understanding of the pathogenesis of psoriasis have led to the development of biologic agents that target T cells and cytokines that play a specific role in the underlying inflammation associated with psoriasis.5,7 Several tumor necrosis factor (TNF)-α inhibitors (etanercept, adalimumab, and infliximab) and an inhibitor of interleukin (IL)-12 and IL-23 (ustekinumab) are currently available for the treatment of moderate-to-severe plaque psoriasis. This article will review the role of IL-17 in the pathophysiology of psoriasis and discuss clinical evidence on the efficacy and safety of selective IL-17 inhibitors in development.
LITERATURE SEARCH METHODS AND RESULTS
A PubMed search was conducted using the search criteria: “psoriasis AND (IL-17 OR interleukin-17)”; limited to title/abstract, English, and publication 2007–July 15, 2013 and updated with relevant publications known to the authors. Abstracts had to be available. The search identified 226 articles (Figure 1), the abstracts of which were evaluated for relevance. A total of 49 preclinical studies, clinical studies, or review articles were considered potentially relevant, and full-text versions were obtained for evaluation and possible inclusion in this review. Of these 49 articles, 22 were selected for inclusion in this review; reasons for exclusion are indicated in (Figure 1).
IL-17 as a Novel Target in the Pathophysiology of Psoriasis
IL-17 was first cloned in 1993, with 6 members of this cytokine family (IL-17A through IL-17F) characterized to date; signaling of the cytokine family is thought to be mediated through 5 receptor members (IL-17RA through IL-17RE).8 The most widely studied of the cytokines include IL-17A, IL-17E (also known as IL-25), and IL-17F. The term IL-17 generally refers to IL-17A, the most prevalent and best characterized form. This cytokine and IL-17F interact through an IL-17RA/IL-17RC complex; IL-17E interacts through an IL-17RA/IL-17RB complex; and IL-17C interacts through an IL-17RA/IL-17RE complex. Ligand-receptor interactions for IL-17B and IL-17D are less well defined. IL-17 mediates production of chemokines and recruitment of neutrophils to sites of inflammation, and it is thought to play a critical role in host immunity against fungal and Staphylococcal infections.8 Despite this immunoprotective role, IL-17 also has pathogenic implications, given its involvement in the regulation of keratinocyte-expressed genes that are involved in the immune mechanisms that are key driving factors in the pathogenesis of psoriasis (Figure 2).9-12
Wilson and colleagues reported that lesional human psoriatic skin had significantly elevated expression of IL-17A and IL-17F mRNA compared with nonlesional human psoriatic